Abstracts
Résumé
La méthylation de l’ADN joue un rôle central au cours du développement et de la cancérogenèse et est essentielle pour le verrouillage de l’expression génique. La récente caractérisation des méthyltransférases de l’ADN (Dnmt) et de leurs partenaires protéiques a permis de lever le voile sur plusieurs mécanismes par lesquels la méthylation réprime la transcription et contribue à la cancérogenèse. Ces nouvelles découvertes ont d’importantes implications aussi bien pour la compréhension de la régulation génique que pour celles des mécanismes de l’oncogenèse. En outre, étant donné le caractère réversible de la méthylation, ces études ouvrent de nouvelles perspectives vers une thérapie épigénétique du cancer.
Summary
DNA methylation plays a pivotal role during development and carcinogenesis and is central to gene silencing. The recent characterization of the DNA methyltransferases - Dnmt- and their protein partners have helped to understand the molecular basis underlying methylation-mediated gene silencing and its involvment in cancer. These discoveries have important implications to the comprehension of transcriptional regulation but also to understand the molecular basis underlying tumorigenesis. Moreover, these studies open new ways towards an epigenetic therapy of cancer.
Appendices
Références
- 1. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science 2001; 293: 1068-70.
- 2. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168-74.
- 3. Jones PA. DNA methylation and cancer. Oncogene 2002; 21: 5358-60.
- 4. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386-9.
- 5. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998; 19: 187-91.
- 6. Taddei A, Almouzni G. Les acétyl-transférases et désacétylases des histones: des co-régulateurs de la transcription, Med Sci 1997; 13: 1205-9.
- 7. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 2000; 24: 88-91.
- 8. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 2000; 25: 338-42.
- 9. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 2000; 25: 269-77.
- 10. Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 2001; 20: 2536-44.
- 11. Deplus R, Brenner C, Burgers WA, et al. Dnmt3L is a transcriptional repressor that recruits histone deacetylase. Nucleic Acids Res 2002; 30: 3831-8.
- 12. Nicolas E, Vandel L, Trouche D. Quand la méthylation des histones entre en scène. Med Sci 2001; 17: 476-9.
- 13. Tamaru H, Selker EU. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 2001; 414: 277-83.
- 14. Jackson JP, Lindroth AM, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 2002; 416: 556-60.
- 15. Fuks F, Hurd PH, Wolf D, Nan X, Bird AP, Kouzarides T. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 2003; 278: 4035-40.
- 16. Tazi J, Bird A. Alternative chromatin structure at CpG islands. Cell 1990; 60: 909-20.
- 17. Peters AH, Mermoud JE, O’Carroll D, et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet 2002; 30: 77-80.
- 18. Ballestar E, Esteller M. The impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis 2002; 23: 1103-9.
- 19. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re- expression of genes silenced in cancer. Nat Genet 1999; 21: 103-7.